Metabolic adaptation in residual triple negative breast cancer following chemotherapy

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ABSTRACT Oxidative phosphorylation (oxphos), a mitochondrial energy generation process, promotes chemotherapeutic resistance in breast and other cancers. In fact, transplantation of mitochondria from tumorigenic cells into non- tumorigenic cells demonstrated these organelles are necessary and sufficient for aggressive phenotypes of triple negative breast cancer (TNBC) cells. Nearly 50% of TNBC patients treated with neoadjuvant (pre-surgical) chemotherapy (NACT; combined anthracyclines, platinums, and/or taxanes) will harbor substantial residual tumor burden, leading to extremely high risk of recurrence and death4. There are no approved targeted therapies for neoadjuvant treatment of non-BRCA-mutant TNBC. Thus, there is an urgent need to find ways to eradicate residual tumor cells. Furthermore, the mechanisms driving metabolic reprogramming in chemoresistant TNBC are unclear. Our comparisons of serial pre- and post-NACT patient-derived xenograft (PDX) and human TNBC biopsies revealed heightened oxphos signatures in residual tumor cells, and we demonstrated oxphos is a unique therapeutic vulnerability of residual TNBC. We observe significantly higher protein levels of the mitochondrial fusion-driving GTPase optic atrophy 1 (OPA1) in post- vs. pre-NACT TNBC biopsies. Furthermore, high expression of mitochondrial fusion-driving proteins in breast cancer is associated with poor survival. The impact of mitochondrial structure, dictated by the balance of mitochondrial fission and fusion, on metabolism varies highly across tumor types. Despite the importance of mitochondria to metabolism, no studies have addressed how mitochondrial structure impacts metabolic states driving TNBC therapeutic responses. Our preliminary data provide evidence that NACT increases mitochondrial fusion and metabolism in vitro and in vivo. We can increase oxphos and NACT resistance in TNBC cells by genetically or pharmacologically perturbing mitochondrial fission with Mdivi-1, a Drp1 inhibitor. Conversely, perturbation of mitochondrial fusion with MYLS22, an OPA1 inhibitor, decreased oxphos and NACT resistance. We hypothesize OPA1-driven mitochondrial fusion mediates an NACT-induced metabolic switch to promote chemoresistance in TNBC cells. To address this, our specific aims are to: 1) Determine if mitochondrial fusion is responsible for chemotherapy- induced oxphos in TNBC, and 2) Target and quantify mitochondrial fusion in residual TNBC mouse models and serial patient biopsies. These results will increase our mechanistic understanding of regulation of the mitochondrial life, as well as mechanisms driving metabolic adaptations in TNBC. Furthermore, our findings will provide additional metabolic therapeutic targets to overcome chemoresistance in residual TNBCs.